Many severe psychiatric disorders of childhood such as autism, mental retardation, and childhood schizophrenia are caused by abnormalities in brain development. In some of these cases, the abnormal neural development is due to a genetic defect. The goal of the research proposed is to identify and study genes that regulate the development of the mammalian brain, in particular the telencephalon. It is likely that study of the basic genetic mechanisms that control neural development will provide a basis for understanding developmental psychiatric disorders. Subtractive hybridization between cDNA libraries will be used to enrich for genes that are preferentially expressed during development of the mouse telencephalon. Genes that are homologous to transcriptional regulators will be identified using PCR and hybridization. Using these methodologies, several cDNAs were cloned in the last year. Highest priority will be given to analysis of one of these genes called TES-l. Preliminary evidence shows that TES-l encodes a homeodomain- containing protein that is transiently expressed during development of the ventral forebrain, which suggests that TES-l encodes a transcriptional activator that may regulate differentiation of the ventral forebrain. Analysis of TES-l will include DNA sequencing, in situ hybridization, and characterization of the genomic DNA.Functional studies will include construction of transgenic mice which express the LacZ gene under the control of the TES-l promoter, and construction of strains of mice containing mutations in TES- l.